PROJECT SUMMARY/ABSTRACT Tremor is the most common movement disorder. It impairs voluntary actions by causing intense shaking during walking, eating, and speaking. The shaking is repetitive and highly rhythmic as the affected body parts ?oscillate? back and forth. Oscillation frequency is a defining feature of tremor; distinct tremors are found in Parkinson's disease, dystonia, and essential tremor (ET). Because tremor disorders have a neurological basis, it implies that specific brain oscillations drive the body to oscillate at the same frequency. However, it is still not clear where in the central nervous system the oscillations begin, and the processes that lead to oscillations in the connected brain regions remain unknown. In ET, which is the most prevalent form of pathological tremor, a hindbrain motor region called the cerebellum has been heavily implicated as the major source of abnormal activity. But, how abnormal cerebellar activity leads to oscillating motions has been challenging to test. This is largely because of the lack of an appropriate animal model. To address this problem, we identified a mouse genetic model that exhibits the core features of ET. We have generated compelling preliminary data showing that the loss of a Purkinje cell gene, Car8, causes an ET-like tremor that mimics the human condition in its frequency, progression with age, and responsiveness to alcohol. Here, we will expand on this work by testing the hypothesis that loss of Car8 function causes cerebellar oscillations that drive tremorgenic activity in the thalamocortical circuit. In our first aim, we will trace the path of the 4- 12Hz tremor oscillations from the cerebellum to the inferior olive, thalamus, and motor cortex in active mice. We will therefore identify the major brain oscillators that contribute to ET pathophysiology. In our second aim, we define the cellular origin of the tremor by testing if genetically and optogenetically altering Purkinje cell firing modulates tremor in Car8 mice. Because cerebellar inhibitory interneurons are also implicated in ET, we will also test if modulating their activity onto Purkinje cells influences tremor. This experiment will address how local circuit wiring impacts network-wide oscillations. Next we will take advantage of the robust connectivity of the cerebellar nuclei with the rest of the motor system, plus the efficacy of deep brain stimulation (DBS). In our third aim, we will use the Car8 mice to test whether the cerebellar nuclei are an effective target for DBS. We hypothesize that directing the DBS to the cerebellar nuclei will prevent the spread of pathological oscillations away from the source. The utility of Car8 as a preclinical model shows promise towards uncovering the mechanisms for how DBS works. Our research has importance to human health because we introduce a multi-disciplinary approach to study a broad spectrum of tremors that are all challenging to define, diagnose, and treat.